Medicinal adjuvants consisting of N-subsitituted-o-toluidine derivatives, and percutaneously absorbable preparations comprising the adjuvants

ABSTRACT

PCT No. PCT/JP95/02033 Sec. 371 Date Mar. 31, 1997 Sec. 102(e) Date Mar. 31, 1997 PCT Filed Oct. 4, 1995 PCT Pub. No. WO96/11022 PCT Pub. Date Apr. 18, 1996A drug solubilizer or drug-absorption accelerator of Formula I is disclosed wherein R1 and R2 are herein defined    &lt;IMAGE&gt;  (I)

TECHNICAL FIELD

This invention relates to a drug solubilizer and a drug-absorptionaccelerator which are for use in administration by percutaneousabsorption of the drug in a preparation for external use, and also to apercutaneously absorbable preparation. More particularly it relates to(1) a drug solubilizer which consists of an N-substituted-o-toluidinederivative and is excellent in drug solubility, safety, stability,compatibility with a base and feeling at the time of use, (2) adrug-absorption accelerator which contains said toluidine derivative asan absorption acceleration effective ingredient, increases the drug inpermeability and transmittability through the skin and is low inirritation to the biomembranes and (3) a percutaneously absorbablepreparation containing said solubilizer and said absorption accelerator.

BACKGROUND ART

There have conventionally been developed ointments, poultices,tape-aids, lotions, suppositories, eye lotions and the like in the fieldof preparations for external use. Among these preparations,percutaneously absorbable preparations have recently attracted publicattention and are arousing an increasing interest in themselves. Thereasons for this are that in cases where a drug, the pharmacologicalaction of which is expected, is administered locally or systemically soas to be percutaneously absorbed, it is advantageously possible to keepthe efficacy of the drug, adjust the rate of absorption thereof easilythereby enabling the prevention of medicinal side effects caused byoverdosing the drug, lessen the influence of metabolism exerted by theeffect of the drug caused by the initial passage thereof through theliver as is experienced in case of oral administration, thereby enablingthe drug to be effectively utilized, and administer comparatively safeeven such a drug as to cause liver troubles and the like. In addition tothe above preparations, there has now been developed a form ofpreparation, called "TTS", having a high function to control the releasethereof.

(1) In these externally usable preparations attempted to bepercutaneously absorbed, it is important to release a drug from a basewhich contains it, that is, it is necessary for the drug to beefficiently transferred from the base to the skin. To this end,generally importance is placed in the state of dissolution of the drugin the base at the stage of designing these preparations. In otherwords, how the drug exists in the base will have remarkable effects onnot only its physicochemical stability but also its release from thebase, percutaneous absorption efficiency and consequent medicinalefficacy. Thus, it comes to be very important when designingpreparations, to select a solubilizer which is excellent insolubilization of the drug and exerts an effect on uniform dispersion ofthe drug into the base.

Solubilizers now used for drugs include fatty acids such as oleic acidand myristic acid, fatty acid esters such as isopropyl myristate andisopropyl palmitate, essence oils such as limonene, peppermint oil andeucalyptus oil, polyhydric alcohols such as polyethylene glycol andpropylene glycol, surface-active agents, glycol salicylate andcrotamiton, among which crotamiton is frequently used as a solubilizerfor difficultly soluble drugs. For example, crotamiton is used as asolubilizer for indomethacin in Japanese Patent Gazette No. Hei 3-3368(or No. 3368/91), as a solubilizer for steroids in Japanese Pat. Appln.Laid-Open Gazette No. Sho 51-73115 (No. 73115/76) and as a precipitationpreventer for valeric acid dexamethasone in Japanese Patent Gazette No.Hei 2-36572. In addition, Japanese Pat. Appln. Laid-Open Gazette No. Sho59-116212 discloses an indomethacin-containing creamy preparationcomprising crotamiton as a solubilizer for the drug.

These solubilizers, however, raise problems as to precipitation of adrug in the crystal form because of shortage of their solubilizability(capability of solubilization), limitation of their use because of theirodor, their bleeding with time due to their poor compatibility with thebase, and their instability such as their decomposition or discolorationwith the lapse of time. Further, these solubilizers cause undesirableside reactions and the like due to their irritation to the skin and theythus exhibit no fully satisfactory results in not a few cases.

(2) On the other hand, absorbability and permeability of the drug aretaken as important factors when percutaneously absorbable preparationsare designed. This is because the healthy skin is naturally protectiveagainst stimuli provided from the outside and, therefore, it makes theabsorption and permeation of a drug therethrough comparativelydifficult. Accordingly, even if the drug is administered in the form ofa percutaneously absorbable preparation, it is difficult at the presentto let the drug be absorbed easily through the skin in such an amount asis necessary for fully realizing an intended medicinal efficacy.

Further, in cases where the drugs are administered to let them beabsorbed not through the skin but through other biomembranes such as themouth, rectum, palate, nose or hypoglottis, there are found many drugswhich are difficultly permeable or penetrable through the biomembraneconcerned depending on the kind of the drugs or which are low inbioavailability.

Thus, there are sought drug-absorption accelerators which fully enhancedrugs in permeability, penetrability and absorbability through the skinand other biomembranes, enable the drugs to exhibit their fullpharmacological effects in their practical service concentration and arelow in local and systemic toxicities and high in usability and safety.

When a drug is attempted to be percutaneously absorbed at the present,there is used an absorption accelerator which enables the drug to beabsorbed in a sufficient amount by weakening the barrier function of thestratum corneum where the absorption is to be effected. Of knownabsorption accelerators, those such as salicylic acid, urea,dimethylsulfoxide and dimethylacetoamide are known for their dissolutionof corneum, and, however, the use of them will not necessarily exhibitsatisfactory percutaneous absorption of drugs. Propylene glycol,glycerin, pyrrolidone sodium carbonate and the like can keep the corneumhumid, but it is hardly appreciated that they are effective inpercutaneous absorption of drugs. Further, as absorption acceleratorsthere are known fatty acid esters such as isopropyl myristate andisopropyl adipate, surfactants such as sodium laurylate andpolyoxyethylene-sorbitan monolaurate, thioglycerol, urea derivatives ormixtures of a pyrrolidone-based compound and halogenated hydrocarbons(Japanese Pat. Appln. Laid-Open Gazette No. Sho 60-13720), calciumthioglycolate (Japanese Pat. Appln. Laid-Open Gazette No. Sho 60-11431),1-substituted azacycloalkane-2-one (Japanese Pat. Appln. Laid-OpenGazette No. Sho 60-37092), crotonyl-N-ethyl-o-toluidine (Japanese Pat.Appln. Laid-Open Gazette No. Hei 2-258720) and the like.

Conventional known drug-absorption accelerators, however, are not yetpowerful enough to enhance the bioavailability of drugs which are low inpermeability and penetrability into the biomembranes, and, thus, they donot provide a practical pharmacological effect in not a few cases. Inaddition, there are some of conventional absorption accelerators, whichthemselves exhibit skin irritation and sensitization and presenttextural discoloration and severe serious side effects due to theirsuccessive administration. Furthermore, they are reported to corrodesynthetic resins because of their property as a powerful solvent,thereby to elute irritative substances, sensitizers and the like fromdrug containers, clothing, haberdashery and the like. Under suchcircumstances, the known absorption accelerators still now leaveproblems as to practicality such as limitations on general applicationof the accelerators and method of use thereof.

In view of the above problem (1) as to conventional techniques, a firstobject of this invention is to provide drug solubilizers having thefollowing excellent characteristics. The solubilizers so provided aresuch that they make drugs difficult to precipitate with time because oftheir excellent capability of solubilizing drugs, are physicochemicallystable without their decomposition, phase separation and unpleasant odorin the base, are an inactive substance without interaction with the drugand are high in safety because of few side reactions such as skinsensitization.

A second object of this invention is to provide drug-absorptionaccelerators which can solve the problems (2) as to the conventionaltechniques. The accelerators so provided are such that they enable drugsto be remarkably enhanced in permeability or penetrability through theskin, are highly safe because of their weak skin irritation and nosensitization and are excellently compatible with the base withoutgiving any change in compatibility between the drug and the base.

Moreover, a third object of this invention is to provide percutaneouslyabsorbable preparations comprising various kinds of drugs and the drugsolubilizer of this invention or the drug-absorption accelerator of thisinvention.

DISCLOSURE OF THE INVENTION

The present inventors made intensive studies in an attempt to solve theabove problems and, as the result of their studies, they have found thatan N-substituted-o-toluidine derivative represented by the followingformula (I) is excellent in solubilizing a wide range of drugs, iseffective even for drugs which have exhibited their unsatisfactorysolubility, dispersibility and transferability to the affected part of apatient when the known solubilizer was used and is alsophysicochemically stable with excellent feeling given when in use. Thisinvention is based on the above finding.

At the same time, it has been found that the drug-absorption acceleratorwhich contains the N-substituted-o-toluidine derivative as adrug-absorption accelerating active component, exhibits a more excellentdrug-absorption accelerating action than conventionally known ones andis, furthermore, lower in irritability to the skin. This invention isalso based on this finding.

The crux of this invention resides in a drug solubilizer consisting ofat least one compound selected from N-substituted-o-toluidinederivatives, in a drug-absorption accelerator containing said at leastone compound as a drug-absorption accelerating active component and in apercutaneously absorbable preparation comprising said drug solubilizerand said drug-absorption accelerator, the N-substituted-o-toluidinederivatives being represented by the following formula (I) ##STR2##wherein R₁ is a lower alkyl group having 1-4 carbon atoms and R₂ is analkyl group having 1-8 carbon atoms.

The N-substituted-o-toluidine derivatives, which are the drugsolubilizers or drug-absorption accelerators of this invention, arecompounds having an amide skeleton. The derivatives themselves havealready been known, and an example wherein the derivative is used as onecomponent of a hair-growing preparation is disclosed in Japanese PatentApplication Laid-Open Gazette No. Hei 2-11509 (No. 11509/90). However,there has not been found any example wherein the derivative is used as adrug solubilizer or drug-absorption accelerator of a preparation forexternal use intended for percutaneous absorption of the drug therefrom.Thus, it was not known until the finding by the present inventors thatthe N-substituted-o-toluidine derivatives exhibited excellentperformances as a drug solubilizer or drug-absorption accelerator inpercutaneously absorbable preparations.

The content of the N-substituted-o-toluidine derivative in thepercutaneously absorbable preparation of this invention is 0.01 to 20%by weight, desirably 0.1 to 20% by weight, more desirably 0.1 to 10% byweight, most desirably 0.5 to 5% by weight based on the total weight ofthe preparation. The use of the derivative in an amount of less than0.01% by weight will fail in attaining a sufficient effect as the drugsolubilizer or drug-absorption accelerator, while the use thereof in anamount exceeding 20% by weight will make it difficult to give stablepreparations.

The drugs to be used in the percutaneously absorbable preparation ofthis invention are not particularly limited but may arbitrarily beselected from known drugs.

First, the drugs to be used in a case where theN-substituted-o-toluidine derivative is used as the drug solubilizerinclude antipyretic-antiinflammatory agents, steroidal antiinflammatoryagents, vasodilators, antiarrhythmic agents, hypotensive agents,antitussive-expectorants, local anesthetics, hormone preparations, drugsfor asthma and nasal allergy, antihistamines, anticoagulants, cerebralvasodilators, drugs for metabolic diseases, vitamin preparations,antifungal agents, hypolipidemic drugs, therapeutic agents for urinationdisorder, hypoglycemic agents, hypnotics and antibiotics.

The antipyretic-antiinflammatory agents include sulindac, tolmetin,oxaprozin, pranoprofen, tiaprofen, suprofen, oxaprozin, etodolac,tenidap, bermoprofen, mofezolac, actarit, ampiroxicam, zaltoprofen,indometacin, salicylic acid, aspirin, acetaminophen, diclofenac,ibuprofen, felbinac, ketorolac, roxoprofen, naproxen, ketoprofen,flufenamic acid, ibufenac, fenbufen, alclofenac, phenylbutazone,mefenamic acid, bendazac, piroxicam, flurbiprofen and pentazocinetartrate. The steroidal antiinflammatory agents include hydrocortisone,prednisolone, fluocinolone acetonide, fludroxycortide,methylprednisolone, hydrocortisone acetate, clobetasone butyrate,dexamethasone, betamethasone acetate, diflucortolone valerate,clobetasol propionate and fluocinonide.

The vasodilators include diltiazem, verapamil, pentaerythritoltetranitrate, dipyridamole, isosorbide dinitrate, nifedipine andnitroglycerin. The antihypertensive-antiarrhythmic agents includepropranolol, atenolol, pindolol, quinidine sulfate, ajmalin, alprenololhydrochloride, metoprolol tartrate, nadolol, timolol maleate anddisopyramide. The hypotensive agents include clonidine hydrochloride,captopril, prazosin hydrochloride, penbutolol sulfate, guanabenz acetateand arotinolol hydrochloride. The antitussive-expectorants includeprocaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide,tulobuterol hydrochloride and formoterol fumarate. The local anestheticsinclude benzocaine, procaine, lidocaine and tetracaine. The hormonepreparations include estrogen, estradiol, estriol, testosterone,norethisterone, progesterone, prostaglandin and insulin. The drugs forasthma and nasal allergy include ketotifen fumarate, azelastinehydrochloride and cromoglicic acid sodium. The antihistamines includecyproheptadine hydrochloride, diphenhydramine hydrochloride, fenbenzaminand mequitazine. The anticoagulants include heparin. The cerebralvasodilators and the drugs for metabolic diseases include vinpocetine,flunarizine hydrochloride, nicaravan, fasudil hydrochloride, vinconatehydrochloride, nicardipine hydrochloride, ifenprodil tartrate andisoxsuprine hydrochloride. The vitamin preparations include alfacalcidoland ergocalciferol. The antifungal agents include fluconazole,neticonazole hydrochloride, terbinafine hydrochloride, ketoconazole,miconazole nitrate and econazole nitrate. The hypolipidemic drugsinclude pravastatin, lovastatin, fluvastatine and simvastatine. Thetherapeutic agents for urination disorder include amsulosinhydrochloride, terazosin hydrochloride, naphthopidil, urapidil andbunazosin hydrochloride. The hypoglycemic agents include glibenclamideand gliclazide. The hypnotics include phenobarbital and amobarbital. Theantibiotics include tetracycline and chloramphenicol.

Although examples of the drug have been given above, the drug is notlimited to them. Further, these drugs can also be used in the form ofmedically acceptable inorganic or organic salts.

Then, a description will now be made of the drug to be used in thepercutaneously absorbable preparation of this invention wherein theN-substituted-o-toluidine derivative is used as the drug-absorptionaccelerator.

The drugs include steroidal antiinflammatory agents such asprednisolone, dexamethasone, hydrocortisone, fluocinolone acetonide,betamethasone valerate, betamethasone dipropionate, clobetasone butyrateand prednisolone succinate; nonsteroidal antiinflammatory agents such asindometacin, diclofenac, ibuprofen, ketoprofen, flufenamic acid,ketorolac, flurbiprofen, felbinac, suprofen, pranoprofen, tiaprofen,roxoprofen, tenidap and nimesulide, and esters thereof; antiallergicagents such as tranilast, azelastine, ketotifen, ibudilast, oxatomide,emedastine and ebastine; antihistamines such as diphenhydramine,chlorpheniramine, promethazine and tripelennamine; central nervoussystem acting drugs such as chlorpromazine, nitrazepam, diazepam,phenobarbital and reserpine; hormones such as insulin, testosterone,norethisterone, norethisterone acetate, methyltestosterone, progesteroneand estradiol; antihypertensive agents such as clonidine, reserpine andguanethidine sulfate; cardiotonics such as digitoxin and digoxin;antiarrhythmic agents such as propranolol hydrochloride, procainamidehydrochloride, ajmalin, pidolol and tulobuterol hydrochloride; coronaryvasodilators such as nitroglycerin, isosorbide dinitrate, papaverinehydrochloride and nifedipine; local anesthetics such as lidocaine,benzocaine, procaine hydrochloride and tetracaine; analgesics such asmorphine, aspirin, codeine, acetanilide and aminopyrine; skeletal musclerelaxants such as eperisone, tizanidine, tolperisone, inaperisone andpridinol mesylate; antifungal agents such as acetophenylamine,nitrofurazone, pentamycin, naphthiomate, miconazole, omoconazole,clotrimazole, butenafine hydrochloride and bifonazole; antineoplasticagents such as 5-fluorouracil, busulfan, actinomycin, bleomycin andmitomycin; therapeutic agents for urination disorder such as terodilinehydrochloride, oxybutynin hydrochloride, prazosin hydrochloride,amsulosin hydrochloride, bunazosin hydrochloride, naphthopidil,urapidil, vamicamide, terazosin hydrochloride and oxybutynin;antiepileptics such as nitrazepam and meprobamate; antiparkinson agentssuch as chlorzoxazone and levodopa; assistants for quitting smoking suchas nicotine; vitamins; and prostaglandin. Of course, the drugs are notlimited to those described above. Further, these drugs can also be usedin the form of medically acceptable organic or inorganic salts.

The amount of drug used is preferably 0.001 to 20% by weight, morepreferably 0.5 to 10% by weight, of the total amount of thepercutaneously absorbable preparation, though it is not particularlylimited.

The dosage form of the percutaneously absorbable preparation of thisinvention is not particularly limited, but may be any one selected fromamong conventional poultice, tape-aid, ointment, gel, cream, gel-likecream, lotion, spray, reserver-having patch, liniment, aerosol and soforth.

The poultice and tape-aid among the percutaneously absorbablepreparations of this invention will now be described below.

In preparing the poultice, a hydrophilic base comprising a water-solublepolymer, a polyhydric alcohol and water is used as a base inconsideration of long-term stability, releasability and percutaneousabsorbability of a drug and safety for the skin.

The water-soluble polymer to be used in the hydrophilic base may be oneor more members suitably selected from the group consisting of gelatin,casein, pullulan, dextran, sodium alginate, soluble starch,carboxystarch, dextrin, carboxymethylcellulose, sodiumcarboxymethylcellulose, methylcellulose, ethyl-cellulose,hydroxyethylcellulose, polyvinyl alcohol, polyethylene oxide,polyacrylic acid, polyacrylamide, polysodium acrylate,polyvinylpyrrolidone, carboxy-vinyl polymer, polyvinyl ether,methoxyethylene-maleic anhydride copolymer, N-vinylacetamide, copolymercomprising N-vinylacetamide and acrylic acid and/or acrylate salt and soforth. The amount of the water-soluble polymer used is 1 to 30% byweight, preferably 1 to 20% by weight, more preferably 1 to 15% byweight, based on the total weight of the preparation. When the amount isless than 1% by weight, the resulting preparation will have too low aviscosity to retain its shape, while when it exceeds 30% by weight, theresulting mixture of the constituents will have a high viscosity tolower the workability in preparing a homogeneous dispersion of theconstituents or in applying the dispersion.

The polyhydric alcohol is one or more members suitably selected from thegroup consisting of polyethylene glycol, propylene glycol, dipropyleneglycol, polypropylene glycol, 1,3-butylene glycol, 1,4-butylene glycol,isobutylene glycol, glycerol, diglycerol, sorbitol and so forth. Theamount of the polyhydric alcohol used is 10 to 90% by weight, preferably10 to 70% by weight, more preferably 20 to 60% by weight. When theamount is less than 10% by weight, the resulting preparation willexhibit poor humectant effect, while when it exceeds 90% by weight, thesolubility of the water-soluble polymer will be adversely affected. Theamount of water used is 10 to 90% by weight, preferably 20 to 80% byweight. The water serves to solubilize the water-soluble polymer tothereby make the polymer develop its thickening, cohesive andshape-retaining properties.

If necessary, the base of the poultice may further contain one or morecrosslinking agents in addition to the above essential components. Thecrosslinking agents include polyvalent metal compounds such as aluminumhydroxide, aluminum chloride, calcium hydroxide, calcium chloride,aluminum sulfate, aluminum ammonium sulfate, aluminum potassium sulfate,magnesium aluminometasilicate and dihydroxyaluminum aminoacetate; andcompounds each having at least two epoxy groups in the molecule such asethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether,propylene glycol diglycidyl ether, polypropylene glycol diglycidylether, polytetramethylene glycol diglycidyl ether, glycerol polyglycidylether, polyglycerol polyglycidyl ether, sorbitol polyglycidyl ether,sorbitan polyglycidyl ether, pentaerythritol polyglycidyl ether,resorcinol diglycidyl ether, neopentyl glycol diglycidyl ether and1,6-hexanediol diglycidyl ether.

Further, the poultice may contain one or more other components suitablyselected from among fillers such as kaolin, zinc oxide, titaniumdioxide, talc, bentonite and synthetic aluminum silicate; antisepticssuch as thymol, methyl paraben and ethyl paraben; antioxidants such asascorbic acid, stearic esters, dibutylhydroxytoluene,butylhydroxyanisole, gallic esters, vitamin E, vitamin E acetate anddisodium edetate; ultraviolet absorbers such as2-hydroxy-4-methoxybenzophenone, ethyl p-aminobenzoate,2-(2-hydroxy-5-methylphenyl) benzotriazole, glycol salicylate, methylsalicylate and phenyl salicylate; and emulsifying agents such as fattyacid esters of sorbitan, fatty acid esters of glycerol, fatty acidesters of decaglycerol, fatty acid esters of polyoxyethylene sorbitan,fatty acid esters of polyethylene glycol and polyoxyethylene alkylethers.

It is essential that the support of the poultice be made of a materialwhich has no influence on the release of a drug, i.e., that the supportneither interacts with a drug nor adsorbs a drug. The support isselected from the group consisting of films and sheets of polyethylene,polypropylene, polyvinyl chloride, polyester, nylon and polyurethane;laminates each comprising one or more members selected from the groupconsisting of these films and sheets and one or more members selectedfrom the group consisting of porous materials, expanded materials andwoven and nonwoven fabrics of these polymers. The release sheet of thepoultice according to this invention may be selected from the groupconsisting of films of polyethylene, polypropylene and polyester;products of release treatment of these films with silicone compounds;release paper and so forth.

The preparation of the poultice will now be described, though thepoultice can be easily prepared by known processes.

For example, a drug is solubilized in the N-substituted-o-toluidinederivative to form a solution (A) which may, if necessary, beincorporated with one or more additives selected from the groupconsisting of a stabilizer, an antioxidant, an ultraviolet absorber, anemulsifying agent, an antiseptic, an antimicrobial and so forth.Separately, a water-soluble polymer is mixed into, dispersed andsolubilized in a polyhydric alcohol and water to form a homogeneouspaste (B). The solution (A) is added to the paste (B) to form ahomogeneous dispersion. This dispersion is spread directly on a supportor alternatively it is once spread on a paper or film treated with areleasing agent and thereafter transferred from the paper or film to asupport by pressing. Thus, a poultice according to this invention isprepared. The above-mentioned order of procedures for mixing the basematerials, drug and other components is just one example, and is notlimited to said order of procedures.

Then, the tape-aid of this invention will now be described. The adhesivebase to be used in making the tape-aid may be suitably selected fromknown ones in consideration of safety for the skin, drug-releasingproperties, adhesion to the skin and so on. Preferable adhesive basesinclude acrylic adhesives, rubber-based adhesives and silicone-basedadhesives.

Particularly preferable acrylic adhesives include homopolymers andcopolymers of alkyl (meth)acrylates wherein the alkyl has 4 to 18 carbonatoms and copolymers of such alkyl (meth)acrylates with other functionalmonomers.

The alkyl (meth)acrylates include butyl acrylate, isobutyl acrylate,hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctylacrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, stearylacrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate,isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate,decyl methacrylate, isodecyl methacrylate, lauryl methacrylate andstearyl methacrylate.

The above functional monomers include hydroxyl group-bearing monomers,carboxyl group-bearing monomers, amido group-bearing monomers, aminogroup-bearing monomers and pyrrolidone ring-bearing monomers. Thehydroxyl group-bearing monomers include hydroxyalkyl (meth)acrylatessuch as 2-hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate.The carboxyl group-bearing monomers include α,β-unsaturated carboxylicacids such as acrylic acid and methacrylic acid; monoalkyl maleates suchas butyl maleate; maleic acid; fumaric acid; and crotonic acid. Further,maleic anhydride as well as maleic acid can also be used as a comonomer.The amido group-bearing monomers include alkyl(meth)acrylamides such asacrylamide, dimethylacrylamide and diethylacrylamide;N-alkoxymethyl(meth)acrylamides such as N-butoxymethylacrylamide andN-ethoxymethylacrylamide; and diacetone acrylamide. The aminogroup-bearing monomers include dimethylaminoethyl acrylate. Thepyrrolidone ring-bearing monomers include N-vinyl-2-pyrrolidone.

The rubber-based adhesives include natural rubber, synthetic isoprenerubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene,polybutadiene, styrene-butadiene copolymers, styrene-isoprene copolymersand styrene-isoprene-styrene block copolymers.

The silicone-based adhesives include those mainly comprisingpolyorganosiloxane or polydimethylsiloxane.

The tackifiers to be used in the tape-aids include rosin andhydrogenated, disproportionated, polymerized or esterified derivativesthereof; terpene resins such as α-pinene and β-pinene; terpene-phenolresins; aliphatic, aromatic, alicyclic or copolymer-type petroleumresin; alkylphenyl resin and xylene resins.

The softeners used in the tape-aid plasticizes and softens the basepolymer to permit the tape-aid to keep adhesion to the skin properly.The softeners include polybutene; polyisobutylene; liquid paraffin;higher fatty acid esters such as isopropyl myristate; silicone oils; andvegetable oils such as almond oil, olive oil, camellia oil, persic oiland peanut oil.

The supports to be used in the tape-aids are preferably ones which donot exert any influence on the release of drugs. The supports may bestretchable or non-stretchable ones. The supports are selected fromsynthetic resin membranes which are films and sheets of polyethylene,polypropylene, polybutadiene, ethylene-vinyl acetate copolymers,polyvinyl chloride, polyester, nylon and polyurethane; or selected fromlaminates, porous membranes, foamed bodies, paper, textiles and nonwovenfabrics of said synthetic resins.

The tape-aid according to this invention can be easily prepared by knownprocesses. For example, a tape-aid based on a synthetic rubber can beprepared by mixing an adhesive base with a softening agent and atackifier under heating at 120° to 160° C. by the use of a mixingmachine such as a kneader or mixer, adding a drug and aN-substituted-o-toluidine derivative to the obtained mixture, andapplying the resulting mixture to a support either by spreading themixture directly on a film of polypropylene or polyester or by spreadingthe mixture on a paper or film treated with a releasing agent andthereafter transferring the spread mixture on the paper or film to adesired support by pressing.

The base polymer of the synthetic rubber-based tape-aid may be selectedfrom conventional ones in consideration of safety for the skin,releasability of a drug and adhesion to the skin. From the standpoint ofthe release characteristics of, for example, a nonsteroidalanti-inflammatory agent, however, it is preferable that the base polymerbe a styrene-isoprene-styrene block copolymer having a particularly lowpolarity. Such block copolymers include Cariflex TR-1107, TR-1111,TR-1112 and TR-1117 (trade names, products of Shell Chemical Co., Ltd.)and Solprene 428 (trade name, a product of Phillips Petroleum Co.,Ltd.). These styrene-isoprene-styrene block copolymers may be each usedtogether with other polymer such as polyisobutylene. Vistanex (tradename, a product of Exxon Chemical Co., Ltd.) is preferably used as thepolyisobutylene.

The softening agent used in the above tape-aid serves to plasticize orsoften the styrene-isoprene-styrene block copolymer used as the basepolymer to allow the tape-aid to keep proper adhesion to the skin. Thesoftening agent may be selected from the group consisting of almond oil,olive oil, camellia oil, persic oil, peanut oil, liquid paraffin and soforth. The amount of the softening agent used is preferably 150 to 350parts by weight per 100 parts by weight of the styrene-isoprene-styreneblock copolymer.

The content of a drug in the above tape-aid is preferably 70 to 1200 μgper cm² of the tape-aid from the standpoints of therapeuticallyeffective release of a drug and availability thereof, though it is notparticularly limited. Preferable proportions of a drug, tackifier,N-substituted-o-toluidine derivative, styrene-isoprene-styrene blockcopolymer and softening agent are as follows.

That is, the tape-aid comprises 0.5 to 10% by weight of a drug, 5 to 70%by weight of a rosin ester derivative, 0.1 to 20% by weight of theN-substituted-o-toluidine derivative, 5 to 40% by weight of astyrene-isoprene-styrene block copolymer and 10 to 75% by weight of asoftening agent, each percentage being based on the total amount.

The acrylic tape-aid can be made by dissolving or dispersing an adhesivebase, a drug, an absorption accelerator and, if necessary, variousadjuvants in a proper solvent, applying the thus obtained solution ordispersion directly to a support and drying the resulting layer to forman application layer having a thickness of 30 to 200 μm. Alternatively,the tape-aid can be made also by applying the solution or dispersion toa release paper for protection, drying the resulting layer and makingthe thus formed application layer adhere to a support. The solvent to beused in the above process is not particularly limited but may be anyorganic solvent which is compatible with all of the constituents such asadhesive base and drug. The solvent includes aromatic hydrocarbons suchas toluene, benzene and xylene; and halogenated hydrocarbons such ascarbon tetrachloride, chloroform and methylene chloride.

Now, brief description will be made of other percutaneously absorbablepreparations such as ointment, gel, cream, gel-type cream, lotion,reserver-having patch, liniment and aerosol according to this invention.

The ointment according to this invention comprises at least higher fattyacid such as myristic acid or an ester thereof, a wax such asspermaceti, a surfactant such as polyoxyethylene and a hydrocarbon suchas hydrophilic vaseline in addition to a drug andN-substituted-o-toluidine derivative.

The ointment can be prepared by, for example, mixing 5 to 15% by weightof a higher fatty acid or an ester thereof with 1 to 10% by Weight of asurfactant, 0.5 to 10% by weight of a drug and 0.5 to 10% by weight ofthe N-substituted-o-toluidine derivative either at room temperature orunder heating, adding 4 to 10% by weight of a wax and 50 to 90% byweight of a hydrocarbon to the obtained mixture, heating or heat-meltingthe resulting mixture, keeping the mixture at 50° to 100° C. to make thewhole mixture a transparent solution, homogenating the solution with ahomomixer, and lowering the temperature of the resulting solution toroom temperature under stirring.

The gel according to this invention comprises at least a lower alcoholsuch as ethanol, water, a gelling agent such as a carboxyvinyl polymerand a neutralizing agent such as triethanolamine in addition to a drugand N-substituted-o-toluidine derivative.

The gel can be prepared, for example, as follows: 0.5 to 5% by weight ofa gelling agent is swollen with at most 55% by weight of water;separately, 0.5 to 10% by weight of a drug is solubilized in 0.5 to 10%by weight of N-substituted-o-toluidine derivative and the obtainedsolution is further solubilized in a mixture comprising at most 40% byweight of a glycol and at most 60% by weight of a lower alcohol; theobtained solution is mixed with the gelling agent swollen above; and theresulting mixture is adjusted to pH4-7 by the addition of a neutralizingagent, thus forming a gel according to this invention.

The cream according to this invention comprises at least a higher fattyacid ester such as myristate, water, a hydrocarbon such as liquidparaffin and an emulsifying agent such as polyoxyethylene alkyl ether inaddition to a drug and N-substituted-o-toluidine derivative.

The cream can be prepared by stirring a mixture comprising a drug, theN-substituted-o-toluidine derivative, a higher fatty acid ester, water,a hydrocarbon and an emulsifying agent in proper amounts.

A gel-like cream has intermediate properties between a gel and a creamand can be prepared by adding a gelling agent such as a carboxyvinylpolymer to components of cream as described above and adjusting theresulting mixture to pH4-8, preferably pH5-6.5 by the addition of aneutralizing agent such as diisopropanolamine.

The gel-like cream according to this invention can be prepared, forexample, as follows: 0.5 to 10% by weight of a drug is solubilized in0.5 to 10% by weight of the N-substituted-o-toluidine derivative and theobtained solution is further solubilized in a mixture comprising at most25% by weight of a higher fatty acid ester and at most 40% by weight ofa lower alcohol, followed by the addition of at most 5% by weight of anemulsifying agent; separately, 0.5 to 5% by weight of a gelling agent isswollen with water; the swollen agent is mixed with the solutionprepared above; and the obtained mixture is homogenized with a homomixerand adjusted to pH4-8 by the addition of a neutralizing agent.

The lotion according to this invention comprises at least a loweralcohol such as ethanol and water and/or a glycol in addition to a drugand N-substituted-o-toluidine derivative.

The lotion can be prepared by stirring a mixture comprising a drug, theN-substituted-o-toluidine derivative, a lower alcohol and water and/or aglycol in proper amounts.

The reserver-having patch according to this invention comprises at least(1) a backing layer, (2) a drug reserving layer, (3) a drug releasinglayer and (4) a pressure-sensitive adhesive layer, wherein the drugreserving layer (2) is a base comprising one mixture selected from thegroup consisting of

(a) mixture comprising at least a glycol, a lower alcohol, water and awater-soluble polymer,

(b) a mixture comprising at least an aliphatic alcohol and a polyhydricalcohol and

(c) a mixture comprising at least a paraffin and a silicon compound,

in addition to a drug and the N-substituted-o-toluidine derivative.

The liniment according to this invention comprises at least an alcoholsuch as ethanol or polyethylene glycol, water and an ester of fatty acidsuch as adipic acid or sebacic acid in addition to a drug and theN-substituted-o-toluidine derivative.

The liniment can be prepared by dissolving 0.5 to 10% by weight of adrug in 0.5 to 10% by weight of the N-substituted-o-toluidine derivativeand mixing the obtained solution with 10 to 70% by weight of an alcohol,at most 55% by weight of water and at most 60% by weight of a fatty acidester under stirring.

The aerosol according to this invention comprises at least a loweralcohol, water and dimethyl ether and/or liquefied petroleum gas inaddition to a drug and N-substituted-o-toluidine derivative, and mayfurther contain an auxiliary drug such as camphor α-tocopherol ormenthol as needed. The aerosol can be prepared by dissolving 0.5 to 10%by weight of a drug in 0.5 to 10% by weight of theN-substituted-o-toluidine derivative, adding a lower alcohol and waterto the obtained solution, charging the obtained mixture into an aerosolcontainer and press-injecting dimethyl ether and/or liquefied petroleumgas as a propellant into the container.

The percutaneously absorbable preparations according to this inventionmay further contain various pharmacologically acceptable additives suchas a stabilizer, an antioxidant, a perfume, a filler, an ultravioletabsorber, an antihistamine, an antiseptic, an antimicrobial agent and anabsorbefacient.

The drug solubilizer of this invention consisting of at least one of theN-substituted-o-toluidine derivatives exhibits excellent solvency for awide range of drugs and is so excellent in heat stability as todecompose little even under heating at high temperature or to generatelittle unpleasant odor.

A percutaneously absorbable preparation comprising the solubilizer and adrug, particularly a sticking-type one, is excellent in stability as thepreparation and exhibits excellent drug-releasing properties for a longperiod, so that the drug can be absorbed into the circulatory systemthrough the skin in amounts enough to exhibit the objective effects.

Although the detailed mechanism of action of how the solubilizerexhibits high solvency for a drug and how the preparation containing itis stabilized has not been elucidated, it is believed that theinteraction between the highly polar amide skeleton and fat-solublealkyl groups of the solubilizer enhances the solvency for a drug andprevents a drug from precipitating in the crystal form. Meanwhile, noskin sensitization due to the solubilizer has been observed.

On the other hand, the drug-absorption accelerator of this inventioncomprising at least one of the N-substituted-o-toluidine derivativesenhances the permeation or transmission of a drug through the skinremarkably, when added to the drug in a proper amount.

When a percutaneously absorbable preparation containing the absorptionaccelerator is applied to the skin, the drug contained in thepreparation can be absorbed easily through the skin. Although thedetailed mechanism of action how this effect is exhibited has not beenelucidated, it is believed that the absorption accelerator acts on thecell membranes of dermal cells to lower the barrier properties thereof.

When a tape-aid or patch is made by the use of the drug-absorptionaccelerator, the absorption accelerator does not exert any adverseeffect on the properties of the adhesive constituting the tape-aid orpatch, so that the tape-aid or the patch can keep its adhesiveness.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1: A view showing the intradermal sensitization test in the neckand back of guinea-pig

FIG. 2: Graphs showing the initial release of drugs from preparations

FIG. 3: Graphs showing the release of drugs from preparations afterbeing allowed to stand at 60° C. for one month after the production

FIG. 4: Graphs showing the penetrability of indomethacin through theskin of hairless mouse

FIG. 5: Graphs showing the penetrability of pindrol through the skin ofhairless mouse

BEST MODE FOR CARRYING OUT THE INVENTION

This invention will be further described by the following Examples,Comparative Examples and Test Examples.

    ______________________________________    Example 1 lotion    (wt. %)    ______________________________________    ethanol             57.0    purified water      34.0    propylene glycol    5.0    N-butanoyl-N-ethyl-o-toluidine                        3.0    ketoprofen          1.0    ______________________________________

The above components were mixed together under agitation thereby toprepare a lotion comprising ketoprofen.

    ______________________________________    Example 2 cream      (wt. %)    ______________________________________    liquid paraffin      10.0    medium chain triacylglycerol                         5.0    polyethylene glycol monostearate                         3.0    carboxyvinyl polymer 1.0    diisopropanolamine   0.4    methyl p-oxybenzoate 0.2    indomethacin         1.0    N-butanoyl-N-ethyl-o-toluidine                         5.0    purified water       balance    ______________________________________

The above components were mixed together under agitation thereby toprepare a cream comprising indomethacin.

    ______________________________________    Example 3 ointment  (wt. %)    ______________________________________    white vaseline      76.0    glycerol monostearate                        10.0    beef tallow         10.0    silicone oil        1.0    N-butanoyl-N-ethyl-o-toluidine                        2.0    flurbiprofen        1.0    ______________________________________

The above components were mixed together under agitation thereby toprepare an ointment comprising flurbiprofen.

    ______________________________________    Example 4 poultice  (wt. %)    ______________________________________    N-butanoyl-N-ethyl-o-toluidine                        1.0    diclofenac          0.5    purified water      48.5    gelatin             8.0    kaolin              1.0    glycerol            35.0    polysodium acrylate 2.0    polyvinyl alcohol   3.0    aluminum hydroxide  1.0    ______________________________________

The above ingredients were solubilized together and agitated thereby toobtain a homogeneous paste. The paste was applied on a polypropylenenonwoven fabric with a spreader to obtain a percutaneously absorbablepreparation layer having a thickness of 1 mm. Then, the preparationlayer was covered with a polypropylene film and cut into pieces eachhaving a predetermined size thereby to obtain intended pharmaceuticalproducts.

    ______________________________________    Example 5 poultice  (wt. %)    ______________________________________    N-butanoyl-N-ethyl-o-toluidine                        2.0    loxoprofen          1.0    thymol              0.1    purified water      62.4    gelatin             3.0    titanium oxide      1.0    glycerol            25.0    polysodium acrylate 3.0    carboxymethyl cellulose                        1.0    ethylene glycol diglycidyl ether                        1.0    sorbitan fatty acid ester                        0.5    ______________________________________

The above ingredients were solubilized together and agitated thereby toobtain a homogeneous paste. The paste was applied on a polyesternonwoven fabric with a spreader to obtain a percutaneously absorbablepreparation layer having a thickness of 0.5 mm. Then, the preparationlayer was covered with a polyethylene film and cut into pieces eachhaving a predetermined size thereby to obtain intended pharmaceuticalproducts.

    ______________________________________    Example 6 poultice  (wt. %)    ______________________________________    N-butanoyl-N-ethyl-o-toluidine                        3.0    ibuprofen           0.5    ethyl paraben       0.2    purified water      42.3    methoxyethylene anhydrous                        5.0    maleic acid copolymer    synthetic aluminium silicate                        3.0    glycerol            40.0    polyacrylic acid    2.0    polyvinyl alcohol   2.5    calcium hydroxide   1.5    ______________________________________

The above ingredients were solubilized together and agitated thereby toobtain a homogeneous paste. The paste was applied on a polyurethane filmwith a spreader to obtain a percutaneously absorbable preparation layerhaving a thickness of 1 mm. Then, the preparation layer was covered witha polyester film and cut into pieces each having a predetermined sizethereby to obtain intended pharmaceutical products.

    ______________________________________    Example 7 poultice   (wt. %)    ______________________________________    N-butanoyl-N-ethyl-o-toluidine                         2.0    ketoprofen           0.5    purified water       36.0    N-vinylacetamide     5.0    glycerol             50.0    polyacrylic acid     3.0    carboxymethyl cellulose                         1.0    magnesium metasilicate aluminate                         1.5    fatty acid esters of glycerol                         1.0    ______________________________________

The above ingredients were solubilized together and agitated thereby toobtain a homogeneous paste. The paste was applied on a polyesternonwoven fabric with a spreader to obtain a percutaneously absorbablepreparation layer having a thickness of 1 mm. Then, the preparationlayer was covered with a polyester film and cut into pieces each havinga predetermined size thereby to obtain intended pharmaceutical products.

    ______________________________________    Example 8 tape-aid  (wt. %)    ______________________________________    styrene-isoprene-styrene                        22.5    block copolymer    polyisobutylene     5.0    rosin ester         15.0    liquid paraffin     56.0    N-butanoyl-N-ethyl-o-toluidine                        1.0    ketotifen           0.5    ______________________________________

The above components were agitated under heating, thereby obtaining apaste. The paste was spread on a support to obtain a tape-aid containingketotifen.

    ______________________________________    Example 9 tape-aid  (wt. %)    ______________________________________    styrene-isoprene-styrene                        25.0    block copolymer    liquid paraffin     59.0    alicyclic saturated 5.0    hydrocarbon resin    N-butanoyl-N-ethyl-o-toluidine                        10.0    diclofenac          1.0    ______________________________________

The above components were mixed by a kneader to obtain a paste.Thereafter, the paste was applied directly on a PBT woven fabric andthen covered with a liner to obtain a tape-aid containing diclofenac.

    ______________________________________    Example 10 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        20.0    block copolymer    liquid paraffin     43.5    polyisobutylene     10.0    rosin ester         21.5    N-butanoyl-N-ethyl-o-toluidine                        4.0    diclofenac          1.0    ______________________________________

The above components were mixed by a mixer to obtain a paste. The pastewas applied on a plastic film previously endowed with releasability andthen covered with a PET woven fabric and pressure-contact transferred toobtain a tape-aid containing diclofenac.

    ______________________________________    Example 11 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        15.0    block copolymer    liquid paraffin     23.0    polyisobutylene     7.0    rosin ester         40.0    N-butanoyl-N-ethyl-o-toluidine                        10.0    ketoprofen          5.0    ______________________________________

The components of the above prescription were mixed together by akneader to obtain a paste. The paste was applied on a plastic filmpreviously endowed with releasability, thereon covered with apolypropylene nonwoven fabric and pressure-contact transferred to obtaina tape-aid.

    ______________________________________    Example 12 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        21.0    block copolymer    liquid paraffin     66.8    rosin ester         7.2    N-butanoyl-N-ethyl-o-toluidine                        4.0    flurbiprofen        1.0    ______________________________________

A tape-aid containing flurbiprofen was obtained in the same manner as inExample 10.

    ______________________________________    Example 13 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        21.0    block copolymer    liquid paraffin     50.0    rosin ester         20.5    N-butanoyl-N-ethyl-o-toluidine                        5.5    loxoprofen          3.0    ______________________________________

The components of the above prescription were mixed together by akneader to obtain a paste. The paste was applied on a plastic filmpreviously endowed with releasability, thereon covered with apolypropylene woven fabric and pressure-contact transferred to obtain atape-aid containing loxoprofen.

    ______________________________________    Example 14 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        22.0    block copolymer    polyisobutylene     8.0    liquid paraffin     46.0    rosin ester         14.0    N-butanoyl-N-ethyl-o-toluidine                        8.0    ketorolac           2.0    ______________________________________

The components of the above prescription were mixed together by akneader to obtain a paste. The paste was applied on a plastic filmpreviously endowed with releasability and, covered thereon with a PBTnonwoven fabric and pressure-contact transferred to obtain a tape-aid.

    ______________________________________    Example 15 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        15.0    block copolymer    polyisobutylene     14.0    liquid paraffin     38.0    rosin ester         26.0    N-butanoyl-N-ethyl-o-toluidine                        5.0    felbinac            2.0    ______________________________________

The components of the above prescription were mixed together by akneader to obtain a paste. The paste was applied on a plastic filmpreviously endowed with releasability, thereon covered with apolypropylene woven fabric and pressure-contact transferred to obtain atape-aid.

    ______________________________________    Example 16 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        27.0    block copolymer    liquid paraffin     55.0    rosin ester         7.0    N-butanoyl-N-ethyl-o-toluidine                        10.0    estradiol           1.0    ______________________________________

The components of the above prescription were mixed together by akneader to obtain a paste. The paste was applied on a plastic filmpreviously endowed with releasability and, covered thereon with a PETfilm and pressure-contact transferred to obtain a tape-aid.

    ______________________________________    Example 17 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        27.0    block copolymer    liquid paraffin     55.0    rosin ester         7.0    N-butanoyl-N-ethyl-o-toluidine                        10.0    isosorbide dinitrate                        1.0    ______________________________________

A tape-aid containing isosorbide dinitrate was obtained in the samemanner as in Example 10.

    ______________________________________    Example 18 tape-aid    (wt. %)    ______________________________________    pressure-sensitive adhesive of                           77.0    acrylic resin solubilizer type    (trade name: NISSETSU PE-300) (solid)    N-butanoyl-N-ethyl-o-toluidine                           15.0    isosorbide dinitrate   8.0    ______________________________________

The above components were mixed together to obtain a paste. The pastewas spread on a support and then freed of the solvent by evaporationthereby to obtain a tape-aid containing isosorbide dinitrate.

    ______________________________________    Example 19 tape-aid   (wt. %)    ______________________________________    silicone adhesive     89.0    (trade name: BIO-PSA X7-2920) (solid)    N-butanoyl-N-ethyl-o-toluidine                          7.0    clonidine             4.0    ______________________________________

The above components were mixed together to obtain a paste. The pastewas spread on a support and then freed of the solvent by evaporationthereby to obtain a tape-aid containing clonidine.

    ______________________________________    Example 20 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    N-butanoyl-N-ethyl-o-toluidine                        4.0    estradiol           1.0    ______________________________________

A tape-aid containing estradiol was obtained in the same manner as inExample 16.

    ______________________________________    Example 21 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        15.0    block copolymer    polyisobutylene     14.0    liquid paraffin     38.0    rosin ester         27.0    N-propanoyl-N-ethyl-o-toluidine                        5.0    estradiol           1.0    ______________________________________

A tape-aid containing estradiol was obtained in the same manner as inExample 16.

    ______________________________________    Example 22 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        15.0    block copolymer    polyisobutylene     14.0    liquid paraffin     38.0    rosin ester         27.0    N-butanoyl-N-ethyl-o-toluidine                        5.0    estradiol           1.0    ______________________________________

A tape-aid containing estradiol was obtained in the same manner as inExample 10.

    ______________________________________    Example 23 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    N-propanoyl-N-ethyl-o-toluidine                        4.0    estradiol           1.0    ______________________________________

A tape-aid containing estradiol was obtained in the same manner as inExample 10.

    ______________________________________    Example 24 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    N-acetyl-N-ethyl-o-toluidine                        4.0    estradiol           1.0    ______________________________________

A tape-aid containing estradiol was obtained in the same manner as inExample 10.

    ______________________________________    Example 25 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    N-acetyl-N-ethyl-o-toluidine                        4.0    testosterone        1.0    ______________________________________

A tape-aid containing testosterone was obtained in the same manner as inExample 16.

    ______________________________________    Example 26 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    N-propanol-N-ethyl-o-toluidine                        4.0    testosterone        1.0    ______________________________________

A tape-aid containing testosterone was obtained in the same manner as inExample 16.

    ______________________________________    Example 27 tape-aid (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    N-butanoyl-N-ethyl-o-toluidine                        4.0    testosterone        1.0    ______________________________________

A tape-aid containing testosterone was obtained in the same manner as inExample 16.

    ______________________________________    Comparative Example 1 tape-aid                        (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     32.0    rosin ester         39.0    estradiol           1.0    ______________________________________

A tape-aid containing estradiol was obtained in the same manner as inExample 10.

    ______________________________________    Comparative Example 2 tape-aid                        (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    crotamiton          4.0    estradiol           1.0    ______________________________________

A tape-aid containing estradiol was obtained in the same manner as inExample 10.

    ______________________________________    Comparative Example 3 tape-aid                        (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    propylene glycol    4.0    estradiol           1.0    ______________________________________

A tape-aid containing estradiol was obtained in the same manner as inExample 10.

    ______________________________________    Comparative Example 4 tape-aid                        (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     32.0    rosin ester         39.0    testosterone        1.0    ______________________________________

A tape-aid containing testosterone was obtained in the same manner as inExample 16.

    ______________________________________    Comparative Example 5 tape-aid                        (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    dimethyl sulfoxide  4.0    testosterone        1.0    ______________________________________

A tape-aid containing testosterone was obtained in the same manner as inExample 16.

    ______________________________________    Comparative Example 6 tape-aid                        (wt. %)    ______________________________________    styrene-isoprene-styrene                        28.0    block copolymer    liquid paraffin     30.0    rosin ester         37.0    crotamiton          4.0    testosterone        1.0    ______________________________________

A tape-aid containing testosterone was obtained in the same manner as inExample 16.

Test Example 1

Drug dissolution test

(Experimental method)

1. Samples were prepared under various conditions (i.e, at varioussolubilizer/drug ratios). Each sample was heated at 120° C. to dissolvethe drug gradually. The heating was discontinued in at most 2 hoursconsidering the stability of drugs and so on (the compound in which thedrug was not dissolved after 2-hour heating was regarded as having nosolvency).

2. After the dissolution, the resulting samples were allowed to stand atroom temperature for two weeks or longer and observed for whether thedrugs were precipitated in the crystal forms or not. The samples notcausing apparently recognizable precipitation were further allowed tostand at 5° C.

The results of the tests on dissolution of ketoprofen, indomethacin,isosorbide dinitrate and estradiol are given in Table 1 (comparisonamong the solubilities of ketoprofen in various solubilizers), Table 2(comparison among the solubilities of indomethacin in varioussolubilizers), Table 3 (comparison among the solubilities of isosorbidedinitrate in various solubilizers) and Table 4 (comparison among thesolubilities of estradiol in various solubilizers). In these Tables,"acetamiton" (invention solubilizer) refers toN-acetyl-N-ethyl-o-toluidine, and "butamiton" (invention solubilizer)N-butanoyl-N-ethyl-o-toluidine.

                  TABLE 1    ______________________________________    Drug:Solubilizer              acetamiton                       butamiton                                EtOH PEG(400)                                            PG  IPM    ______________________________________    1:2.5     ◯                       ◯                                ◯                                     ◯                                            ◯                                                *    1:1.3     ◯                       ◯                                ◯                                     Δ                                            Δ    1:1.0     ◯                       ◯                                ◯                                     *      Δ    1:0.8     ◯                       ◯                                ◯                                            Δ    1:0.7     ◯                       ◯                                ◯                                            Δ    1:0.5     ◯                       ◯                                ◯                                            *    1:0.4     ◯                       ◯                                *    1:0.3     ◯                       Δ    1:0.2     Δ  *    ______________________________________     Note:     * → Deposition before 1 week     Δ → Deposition between 1 to 2 weeks     ◯ → No Deposition after 2 weeks

                  TABLE 2    ______________________________________    Drug:Solubilizer              acetamiton                       butamiton                                EtOH PEG(400)                                            PG  IPM    ______________________________________     1:33.0   ◯                       ◯                                ◯                                     ◯                                            ◯                                                *     1:10.0   ◯                       ◯                                *    ◯                                            Δ    1:7.0     ◯                       ◯ ◯                                            *    1:5.0     ◯                       ◯ ◯    1:3.3     ◯                       ◯ Δ    1:2.5     ◯                       ◯ Δ    1:1.3     ◯                       Δ       *    1:1.0     *        *    ______________________________________     Note:     * → Deposition before 1 week     Δ → Deposition between 1 to 2 weeks     ◯ → No Deposition after 2 weeks

                  TABLE 3    ______________________________________    Drug:Solubilizer              acetamiton                       butamiton                                EtOH PEG(400)                                            PG  IPM    ______________________________________     1:33.0   ◯                       ◯                                ◯                                     ◯                                            ◯                                                ◯     1:10.0   ◯                       ◯                                ◯                                     ◯                                            Δ                                                *    1:7.0     ◯                       ◯                                ◯                                     ◯                                            *    1:5.0     ◯                       ◯                                *    ◯    1:3.3     ◯                       ◯ Δ    1:2.5     ◯                       ◯ *    1:1.3     ◯                       Δ    1:1.0     Δ  Δ    1:0.8     *        *    ______________________________________     Note:     * → Deposition before 1 week     Δ → Deposition between 1 to 2 weeks     ◯ → No Deposition after 2 weeks

                  TABLE 4    ______________________________________    Drug:Solubilizer              acetamiton                       butamiton                                EtOH PEG(400)                                            PG  IPM    ______________________________________     1:33.0   ◯                       ◯                                ◯                                     ◯                                            ◯                                                ◯     1:10.0   ◯                       ◯                                *    Δ                                            *   *    1:7.0     ◯                       ◯ *    1:5.0     ◯                       ◯    1:3.3     ◯                       ◯    1:2.5     ◯                       Δ    1:1.3     *        *    ______________________________________     Note:     * → Deposition before 1 week     Δ → Deposition between 1 to 2 weeks     ◯ → No Deposition after 2 weeks

It can be understood from the results given in Tables 1 to 4 that theN-substituted-o-toluidine derivatives are superior to representativesolubilizers now used conventionally in solvency power for drugs andexhibit excellent solvency action for a wide range of drugs.

Test Example 2

Heat stability test

(Experimental method)

1. Stopped sample tubes each containing 100 mg of a solubilizer thereinwere prepared and heated on a hot plate at 180° C. for 5 hours.

2. The resulting sample solubilizers were observed for state. Further,the sample solubilizers were subjected to GC analysis both before andafter the heating to determine the rates of solubilizers remaining afterthe heating.

In the Table, "acetamiton" refers to N-acetyl-N-ethyl-o-toluidine, and"butamiton" N-butanoyl-N-ethyl-o-toluidine.

                  TABLE 5    ______________________________________              acetamiton                      butamiton   crotamiton    ______________________________________    State of solubilizer                pale-yellow                          pale-yellow dark brown                transparent                          transparent    rate of solubilizer                99.0%     98.5%       81.5%    remaining    ______________________________________     Note:     Crotamiton generates a strong unpleasant odor after heating.

As apparent from the results given in Table 5, theN-substituted-o-toluidine derivatives of this invention are superior tocrotamiton in heat stability.

Test Example 3

Test of preparation for stability

The tape-aids of Examples 20, 23 and 24 and Comparative Examples 1 to 3were stored at 5° C. for seven weeks, while they were observed with thelapse of time to find whether the drug crystallized or not. The resultsare given in Table 6.

                  TABLE 6    ______________________________________    Sample  initial                   1 week  2 weeks                                  3 weeks                                        4 weeks                                               7 weeks    ______________________________________    Ex. 20  ◯                   ◯                           ◯                                  ◯                                        ◯                                               ◯    Ex. 23  ◯                   ◯                           ◯                                  ◯                                        ◯                                               ◯    Ex. 24  ◯                   ◯                           ◯                                  ◯                                        ◯                                               ◯    Comp. Ex. 1            *    Comp. Ex. 2            ◯                   ◯                           *    Comp. Ex. 3            ◯                   *    ______________________________________     ◯: no crystallization was found     *: crystallization was found

As apparent from the results in Table 6, the tape-aids of Examples 20,23 and 24 each containing the N-substituted-o-toluidine derivativecontained estradiol in its solubilized state in the base even after thelapse of seven weeks, while the tape-aid of Comparative Example 1containing no solubilizer, that of Comparative Example 2 containingcrotamiton and that of Comparative Example 3 containing propylene glycolsuffered from the crystallization of estradiol in their respectivebases. Thus, the above results supported the usefulness ofN-substituted-o-toluidine derivatives as the solubilizers for estradiol.

Test Example 4

Skin sensitization test

N-substituted-o-toluidine derivatives of this invention were subjectedto the skin sensitization test according to the maximization methodwherein crotamiton was used as a comparative solubilizer.

<Test compounds and control>

(1) crotamiton

(2) N-acetyl-N-ethyl-o-toluidine (hereinafter referred to as"acetamiton")

(3) N-butanoyl-N-ethyl-o-toluidine (hereinafter referred to as"butamiton")

(4) 2,4-dinitrochlorobenzene (DNCB; known skin sensitizer)

<Test animal>

Hartley female guinea pigs (weight: 320 to 400 g) were used in thefollowing groups:

crotamiton-sensitized group, acetamiton-sensitized group,butamiton-sensitized group, DNCB-sensitized group and non-sensitizedgroup (n=7 with respect to each of the groups)

<Administration>

(1) Intradermal sensitization

On the day before administration, the neck and back of each guinea pigwere shorn to set up a section (ca. 2×4 cm). As shown in FIG. 1, points1 to 3 were fixed in the section.

An emulsion comprising Freund's complete adjuvant (FCA) and distilledwater for injection at a ratio of 1:1 was intradermally administered atthe right and left points 1; a 10% (w/v) solution of a test compound inpropylene glycol or a 0.1% (w/v) solution of DNCB therein at the rightand left points 2; and an emulsion comprising a 20% (w/v) solution of atest compound in FCA or a 0.2% (w/v) solution of DNCB in FCA anddistilled water for injection at a ratio of 1:1 at the right and leftpoints 3, each in an amount of 0.05 ml per point.

(2) Percutaneous sensitization

One week after the beginning of sensitization, 0.2 g of a white softparaffin ointment containing 10% of sodium laurate was applied to theintradermally sensitized section; and the next day, the ointment wasremoved with alcohol. Thus, pretreatment was conducted. Then, 0.2 ml ofa solution of a test compound (40%, w/v) in ethanol (70%, v/v) or asolution of DNCB (1%, w/v) therein was applied to a filter paper (2×4cm) and the resulting filter paper was stuck to the sensitized sectionocclusively for 48 hours. The non-sensitized group of guinea pigs werenot subjected to any treatment.

(3) Provocation

Three weeks after the beginning of sensitization, an adhesive plasterfor patch test coated with 0.2 ml of a solution of a test compound (30%,w/v) in ethanol (70%, v/v) or with 0.2 g of a white soft paraffinointment containing 0.1% (w/v) of DNCB was stuck to the right side ofabdomen of each guinea pig, while one coated with a 70% (v/v) ethanolsolution or with a white soft paraffin ointment was stuck to the leftside thereof in the same amount as above. Thus, the 24-hour closed testwas conducted. In a similar manner as above, adhesive plasters for patchtest coated with 0.2 ml of a solution of a test compound (30%, w/v) inethanol (70%, v/v) and with 0.2 ml of 70% (v/v) ethanol respectivelywere stuck respectively to the right and left sides of abdomen ofnon-sensitized group of guinea pigs to conduct 24-hour closed test.

(4) Evaluation

24 and 48 hours after the peeling of the plaster, the guinea pigs wereevaluated for dermoreaction according to the criteria specified in Table7 (findings of skin and score).

                  TABLE 7    ______________________________________    Degree of skin response                           Score    ______________________________________    no change recognizable with the naked eye                           0    slight or sparse erythema                           1    medium erythema        2    significant erythema and edema                           3    ______________________________________

Whether each test compound sensitizes the skin or not was judged bycomparison with the DNCB-sensitized group and the non-sensitized group.The results are given in Table 8.

                                      TABLE 8    __________________________________________________________________________               Number            Percentage               of guinea                       Score     of positive                                      Average    Sensitizer         Provocative               pigs Time                       0  1 2  3 reaction                                      score    __________________________________________________________________________    crotamiton         crotamiton               7    24 7  0 0  0 0    0                    48 3  4 0  0  57.1                                        0.57         EtOH  7    24 7  0 0  0 0    0                    48 7  0 0  0 0    0    acetamiton         acetamiton               7    24 7  0 0  0 0    0                    48 7  0 0  0 0    0         EtOH  7    24 7  0 0  0 0    0                    48 7  0 0  0 0    0    butamiton         butamiton               7    24 6  1 0  0  14.3                                        0.14                    48 6  1 0  0  14.3                                        0.14         EtOH  7    24 7  0 0  0 0    0                    48 7  0 0  0 0    0    DNCB DNCB  7    24 0  0 1  6 100    2.86                    48 0  0 1  6 100    2.86         white soft               7    24 7  0 0  0 0    0         paraffin   48 7  0 0  0 0    0    No   crotamiton               7    24 7  0 0  0 0    0    treatment       48 7  0 0  0 0    0         acetamiton               7    24 7  0 0  0 0    0                    48 7  0 0  0 0    0         butamiton               7    24 7  0 0  0 0    0                    48 7  0 0  0 0    0         EtOH  7    24 7  0 0  0 0    0                    48 7  0 0  0 0    0    __________________________________________________________________________

It can be understood from the above results that acetamiton andbutamiton do not sensitize the skin or the sensitization with them ifany, is lighter and much weaker than that with crotamiton.

Test Example 5

Drug-release test

The tape-aids made in Examples 20 and 23 and Comparative Examples 1 and2 were examined for release of drug into water. This experiment was madeon both the samples just after production and the samples which had beenallowed to stand at 60° C. for one month to thereby determine thestabilities of the preparations with the lapse of time. The preparationsused are those containing estradiol (0.8 mg/10 cm²). The results aregiven in FIG. 2 (just after production) and FIG. 3 (after allowed tostand at 60° C. for one month).

It can be understood from FIGS. 2 and 3 that the preparations made inExamples 20 and 23 exhibit more excellent drug-releasing properties thanthose of the preparations made in Comparative Examples 1 and 2 evenafter they have been allowed to stand at 60° C. for one month.

Test Example 6

Penetration test using hairless mouse skin

(Experimental method)

The penetration of drugs was determined by the diffusion cell methodusing a piece of skin from the back of a female hairless mouse (aged 7weeks).

Indomethacin (IM) and pindolol (PID) were used as the drugs (temperatureof measurement: 22° C.). 0.5 ml of a solution containing a drug wasadded to the donor phase and the amount of the drug penetrating into thereceptor phase was determined by high-performance liquid chromatography(HPLC). The solvents of the donor phase and the receptor phase were 50%ethanol/phosphate buffer (EtOH/PB, pH7.4) and 10% ethanol/phosphatebuffer (EtOH/PB, pH7.4), respectively.

Among the N-substituted-o-toluidines,

N-acetyl-N-ethyl-o-toluidine (ACT)

N-propanoyl-N-ethyl-o-toluidine (PRT) and

N-butanoyl-N-ethyl-o-toluidine (BUT)

were used as drug-absorption accelerators and examined fordrug-absorption accelerating effect in an aqueous system. In thisexamination, crotamiton (Cro.) and dimethyl sulfoxide (DMSO) were usedas comparative compounds. The compositions of the donor phases are givenin Tables 9 and 10.

                  TABLE 9    ______________________________________    In the case of indomethacin    Sample No.            IM     EtOH   PB   ACT  PRT  BUT  Cro. DMSO    ______________________________________    Control 0.5    49.75  49.75    Test Ex. 1-A            0.5    48.5   48.5 2.5    Test Ex. 1-B            0.5    48.5   48.5      2.5    Test Ex. 1-C            0.5    48.5   48.5           2.5    Test Ex. 1-D            0.5    48.5   48.5                2.5    Test Ex. 1-E            0.5    48.5   48.5                     2.5    ______________________________________

                  TABLE 10    ______________________________________    In the case of pindolol    Sample No.            PID    EtOH   PB   ACT  PRT  BUT  Cro. DMSO    ______________________________________    Control 0.1    49.75  49.75    Test Ex. 1-F            0.1    47.45  47.45                               5.0    Test Ex. 1-G            0.1    47.45  47.45     5.0    Test Ex. 1-H            0.1    47.45  47.45          5.0    Test Ex. 1-I            0.1    47.45  47.45               5.0    Test Ex. 1-J            0.1    47.45  47.45                    5.0    ______________________________________

The results are given in FIGS. 4 and 5. It can be understood from theresults that the N-substituted-o-toluidine derivatives of this inventionexhibit remarkable drug-absorption accelerating effect, when added todrugs.

Test Example 7

Percutaneous absorbability test using rabbit skin

(Experimental method)

Japanese white rabbits (male, weight: ca. 2.5 to 3.0 kg) were used ingroups of six. The rabbits were shorn by the use of an electric hairclipper and an electric razor, and the testosterone-containing tape-aids(7 cm ², plaster weight: 80 mg) made in Examples 25 to 27 andComparative Examples 4 to 6 were stuck to the back skins of theresulting rabbits occlusively. After the lapse of predetermined times,the tape-aids were peeled and examined for the amounts of drug remainingin the preparations by HPLC.

Method for determining the amount: Each peeled sample was extracted with70 ml of ethanol under reflux for 3 hours; ethanol was added to theextract to make up to a total volume of 100 ml; and the resultingsolution was used as the sample for HPLC.

Conditions of HPLC:

    ______________________________________    mobile phase                0.55:0.45 mixture of                0.2% acetic acid/water with acetonitrile    absorption wavelength                241 nm    column      TSK gel ODS-80TM    flow rate   1.0 ml/min    Absorbability (%):                100 - (amt. of remaining drug/initial amt.) × 100                (each percutaneous absorbability was                calculated by the above equation)    ______________________________________

The results are given in Table 11.

                  TABLE 11    ______________________________________    Test     Rate of absorption through the back skin of rabbit (%)    preparation             8 hours after   24 hours after    ______________________________________    Ex. 25   24.55 ± 9.64 42.54 ± 11.56    Ex. 26   23.21 ± 9.23 35.96 ± 10.21    Ex. 27   21.36 ± 11.83                             31.08 ± 13.67    Comp. Ex. 6             12.32 ± 7.66 19.54 ± 11.63    Comp. Ex. 5             5.35 ± 4.84  12.94 ± 9.57    Comp. Ex. 4             1.56 ± 1.17  3.36 ± 2.16    ______________________________________

As apparent from the results given in Table 11, the compounds of thisinvention exhibit remarkable increases in the percutaneous absorbabilityof testosterone as compared with the control, and are superior to thecomparative compounds in drug-absorption accelerating effect. In thisexperiment, no abnormality such as erythema or edema was observed in theareas to which the tape-aids containing the compounds of this inventionwere applied.

Test Example 8

Test for irritancy to the skin

The tape-aids made in Examples 25 to 27 and Comparative Examples 4 and 6were examined for irritancy to the human skin.

The testing method is as follows.

Subjects: forty healthy male adults (age: 26 to 35)

Testing method: Each tape-aid was examined according to 48-hour closedpatch test by punching circular pieces having a diameter of 15 mm out ofeach tape-aid, sticking the pieces to the upper backs of the subjectsand covering the pieces with microporous tapes (mfd. by MinnesotaMinning and Manufacturing Co.). After 48 hours, the tape-aids werepeeled off. After the lapse of one and 24 hours from the peeling, thestate of the skin was observed to evaluate the irritancy of eachtape-aid to the skin. The results are given in Table 13 (the criteriaand the equation for calculating skin irritation value are given inTable 12).

                  TABLE 12    ______________________________________    Skin irritation evaluating criteria    Degree of skin response                       Evaluation                                Score    ______________________________________    no change          -        0.0    slight rubefaction ±     0.5    obvious rubefaction                       +        1.0    papule, edema      ++       2.0    ______________________________________     ##STR3##

                                      TABLE 13    __________________________________________________________________________                            Percentage of    Lapse of                positive reaction                                    Skin    time after              (%)     irritation    Sample         peeling off              ++ + ±                      - Total                            ++ and +                                 ±                                    value    __________________________________________________________________________    Ex. 25          1 hour              0  0 5  35                        40  0.0  12.5                                    6.3         24 hours              0  0 2  38                        40  0.0   5.0    Ex. 26          1 hour              0  0 3  37                        40  0.0   7.5                                    5.0         24 hours              0  0 1  39                        40  0.0   2.5    Ex. 27          1 hour              0  0 3  37                        40  0.0   7.5                                    3.8         24 hours              0  0 1  39                        40  0.0   2.5    Comp.          1 hour              0  1 7  32                        40  2.5  20.0                                    11.3    Ex. 4         24 hours              0  0 2  38                        40  0.0   5.0    Comp.          1 hour              0  0 5  35                        40  0.0  12.5                                    7.5    Ex. 6         24 hours              0  0 4  36                        40  0.0  10.0    __________________________________________________________________________

As apparent from the results given in Table 13, the preparationscontaining drug-absorption accelerators of this invention exhibit lowerskin irritation values than that of the preparation not containing anydrug-absorption accelerator. Further, they exhibit skin irritationequivalent to that of the preparation containing crotamiton which hasbeen conventionally used because it is known for its low skinirritation. Therefore, the drug-absorption accelerators of thisinvention are suitably usable for external preparations.

Industrial Applicability

As described above, the drug solubilizers of this invention eachconsisting of at least one of the N-substituted-o-toluidine derivativesare excellent in solvency for drugs and exhibit high safety, stabilityand compatibility with a base. Accordingly, the percutaneouslyabsorbable preparations containing the solubilizers are improved indrug-releasing properties and percutaneous absorbability, so that thesolubilizers are useful for pharmaceutical preparations for externaluse.

On the other hand, the drug-absorption accelerators of this inventioneach comprising at least one of the N-substituted-o-toluidinederivatives remarkably enhance the permeation or transmission of drugsthrough the skin, when added to the drugs in proper amounts. Further,they are lowly irritant to the skin and cause little skin sensitization,thus being extremely safe. Furthermore, they are excellent incompatibility with a base and have little adverse effect on thecompatibility of a drug with a base, so that the preparations containingthem are protected from precipitation of a drug in the crystal form.

The percutaneously absorbable preparations each comprising a drug and anN-substituted-o-toluidine derivative of this invention are very usefulas topical preparations which are expected to exhibit pharmacologicaleffects locally in skin, nose, cavity of mouth, rectum, vagina and soon, or as general drugs which are expected to exhibit systemicpharmacological effects.

What is claimed is:
 1. A solubilizer for use with a drug and consisting of at least one compound selected from N-substituted-o-toluidines represented by the following formula (I): ##STR4## wherein R₁ is a lower alkyl group having 1 to 4 carbon atoms and R₂ is an alkyl group having 1 to 8 carbon atoms.
 2. A percutaneously absorbable preparation comprising the solubilizer of claim 1 and a drug.
 3. A percutaneously absorbable preparation according to claim 2, wherein the solubilizer is present in an amount by weight of 0.01 to 20% of the total weight of the preparation.
 4. An absorption accelerator for use with a drug and consisting of at least one compound selected from N-substituted-o-toluidines represented by the following formula (I): ##STR5## wherein R₁ is a lower alkyl group having 1 to 4 carbon atoms and R₂ is an alkyl group having 1 to 8 carbon atoms.
 5. A percutaneously absorbable preparation comprising the accelerator of claim 4 and a drug.
 6. A percutaneously absorbable preparation according to claim 5, wherein the accelerator is present in an amount by weight of 0.1 to 20% of the total weight of the preparation.
 7. A percutaneously absorbable preparation according to claim 2, which has a dosage form selected from the group consisting of poultice, ointment, gel, cream, gel-like cream, lotion, spray, tape-aid, reserver patch, liniment and aerosol.
 8. A percutaneously absorbable preparation according to claim 3, which has a dosage form selected from the group consisting of poultice, ointment, gel, cream, gel-like cream, lotion, spray, tape-aid, reserver patch, liniment and aerosol.
 9. A percutaneously absorbable preparation according to claim 5, which has a dosage form selected from the group consisting of poultice, ointment, gel, cream, gel-like cream, lotion, spray, tape-aid, reserver patch, liniment and aerosol.
 10. A percutaneously absorbable preparation according to claim 6, which has a dosage form selected from the group consisting of poultice, ointment, gel, cream, gel-like cream, lotion, spray, tape-aid, reserver patch, liniment and aerosol. 